Cancer patients undergoing chemotherapy, radiation, or both experience significant fatigue during treatment, which has a profound effect on quality of life and the patient's ability to receive the prescribed treatment. We hypothesize that treatment induced pro-inflammatory cytokine production plays an important etiological role in cancer treatment related fatigue. There are several lines of evidence that support our hypothesis. First, in addition to fatigue, cancer patients undergoing treatment often experience several other symptoms including anorexia, cachexia, pain, sleep disturbance, depression, and anemia, which can impact the subjective sensation of fatigue. There is now considerable evidence that the inflammatory cytokines IL-1[unreadable], TNF-a and IL-6 play a significant role in the etiology of these symptoms. In this regard CTRF may be homologous to the fatigue associated with sickness behavior, a normal response to infection or tissue injury. The peripheral production of IL-1[unreadable], TNF-a and IL-6 triggers their production in the brain and many of the behavioral consequences of sickness behavior are mediated by their action or production within the brain. Thus, to determine the potential role of IL-1[unreadable], TNF-a and IL-6 in CTRF we must examine changes in the levels of these cytokines during treatment not only in the blood but also in the brain. Second, mechanistically distinct cytotoxic systemic antineoplastic agents and radiation have been shown to induce the production of inflammatory cytokines both in experimental systems and in clinical populations. Third, fatigue is a common symptom in chronic inflammatory conditions such as rheumatoid arthritis and treatment with cytokine blockers can reduce fatigue levels associated with these conditions. In this 2-year proposal we will utilize a pre-clinical and clinical approach to examine the relationship between cancer treatment, inflammatory cytokines and CTRF. In the preclinical approach in Aim 1 we will utilize a previously established mouse treatment model, based on animal models of sickness behavior, which will allow us to determine the relationship between cancer treatment, plasma and brain cytokine levels, and CTRF. This study will run in parallel to a clinical study, in which we will examine the relationship between changes in plasma cytokine levels and changes in fatigue and activity level in cancer patients undergoing treatment; confronting some of the limitations in previous studies on this subject. This "bench to bedside" approach to understanding the cause of CTRF arises from a unique interdisciplinary collaboration among molecular, behavioral, and clinical investigators all working at various points within the spectrum of cancer research at our institution and hence, represents a major innovation in cancer symptom research. In this two-year proposal we plan to address the following aims: 1) Determine the relationship between fatigue and inflammatory cytokine levels in a mouse prostate cancer model of external beam radiation therapy (EBRT), and 2) Determine the relationship between fatigue and plasma inflammatory cytokine levels in prostate cancer patients undergoing EBRT for prostate cancer. [unreadable] [unreadable] [unreadable]